CN1929840B - 晶体形式的8-羟基-5-[(1r)-1-羟基-2-[[(1r)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1h)-喹啉酮单盐酸盐及其制备方法 - Google Patents
晶体形式的8-羟基-5-[(1r)-1-羟基-2-[[(1r)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1h)-喹啉酮单盐酸盐及其制备方法 Download PDFInfo
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Abstract
本发明涉及晶体形式的式(I)的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐,它具有适当的特性以用于与适当载体或赋形剂组合制备用于吸入的药物组合物。本发明还涉及所述化合物的制备方法。
Description
发明领域
本发明涉及晶体形式的式(I)的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐:
本发明还涉及对化合物(I)结晶分离的方法,和它用于与适当载体或赋形剂组合制备用于吸入的药物组合物的用途。
发明背景
8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]2(1H)-喹啉酮单盐酸盐在欧洲专利EP 0 147 719中作为提供有效的β-2-肾上腺素受体刺激作用的支气管扩张药是已知的。
该化合物,还已经被定义为8-羟基-5-{(1R)-1-羟基-2-[N-((1R)-2-(对甲氧苯基)-1-甲基乙基)氨基]乙基}喹诺酮盐酸盐,并被称为TA 2005,申请人已经在实验代码CHF 4226下对其进行 了进一步开发。
现有技术
TA 2005的制备方法描述在EP 0 147 719的实施例4中。特别地,在步骤(3-a)中报道了分离粗产物的方法,其中,在3.5g 8-苯甲氧基-5-{(1R)-1-羟基-2-[N-((1R)-2-(对甲氧苯基)-1-甲基乙基)氨基]乙基}喹诺酮盐酸盐的四氢呋喃(100ml)溶液和水(10ml)催化氢化后,通过过滤将获得的不溶性物质收集起来,并用10%乙醇水溶液洗涤。合并滤液和洗出液,减压浓缩合并的溶液以除去溶剂。用乙醇、水和异丙醚的混合物使剩余物结晶,过滤收集晶状沉淀。得到2.38g 8-羟基-5-{(1R)-1-羟基-2-[N-((1R)-2-(对甲氧苯基)-1-甲基乙基)氨基]乙基}喹诺酮盐酸盐的无色晶体。
产率是83%,最终产物具有下列特征:
熔点:170.0-171.5℃(分解)
[α]D 22-64.40°(c=1.00,甲醇)
IR vmax nujol(cm-1):3300(宽峰),1640,1610,1600。
发明目的
本发明涉及晶体形式的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐,它具有与适当载体或赋形剂组合制备用于吸入的药物组合物的适当特性。
为了简便,该化合物在下文中也将用代码CHF 4226表示。
本发明的化合物优选通过吸入给药。
其中的活性化合物是固体形式的吸入制剂包括:干粉组合物,它通过干粉吸入器(DPI)进行递送;气雾剂组合物,它在抛射气体中包含细微药物颗粒的混悬体,通过加压计量吸入器(pMDI)进行递送;和水混悬液形式的气雾剂组合物,它通过喷雾器进行递送。
这种给药途径的效力受到制造适当一致的剂量供给肺部所遇到的 问题的限制。
最重要的特征之一是确保活性化合物在制剂中均匀分布,尤其是当该活性化合物高度有效而且不得不以低剂量给药时。
而且,组合物中的固体化合物应当尽可能的纯净,并具有所需的化学和物理稳定性。
另外,在吸入组合物中,固体状态的活性化合物应当以控制粒径的细微分散颗粒的形式存在,粒径的质量中位直径大约不超过10μm,优选6μm,更优选5μm,以实现最大渗透到肺中。
所述颗粒用诸如微粉化或研磨的技术常规制备。
这种技术会生产出这样的颗粒,该颗粒具有部分无定形结构,并且当处于不同环境条件下和/或进行药物组合物制备时易于改变其结构。
因此,活性化合物的颗粒应当具有足够的结晶度,以在研磨或微粉化操作过程中高度稳定,并且在后来的制药应用中也充分稳定。
因此,本发明的目的是提供稳定结晶性的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐。
本发明的另一个目的是提供制备具有足够结晶度的化合物的方法。本发明的化合物是化学和物理稳定的,并保持相同的结晶度,在已经进行了微粉化或研磨操作之后也能保持。
在现有技术中,为了获得8-羟基-5-{(1R)-1-羟基-2-[N-(1R)-2-(对甲氧苯基)-1-甲基乙基)氨基]乙基}喹诺酮盐酸盐,在收集了粗产物并用10%乙醇水溶液洗涤之后,合并滤液和洗出液,减压浓缩合并的溶液以除去溶剂,用乙醇、水和异丙醚的混合物使剩余物结晶,过滤收集晶状沉淀,但现有技术没有给出如何进行结晶操作的教导。
现已发现在所述结晶方法中,其中,除去溶剂后获得的剩余物通过加热溶于乙醇和水(95∶5)的混合物中,并且减压浓缩溶液以除去部分溶剂,溶液减少的体积是关键性的。确实已经发现溶液应当浓缩至 等于或大于最初体积1/3的体积。而且,异丙醚必须在不少于5分钟的时间内,在大于30℃的温度下缓慢加至浓缩溶液中。
以上特定条件可以获得均质溶液,其中发生均匀和有规则的晶体生长。
事实上已经发现,如果粗产物的浓缩体积太小,尤其是小于它最初体积的1/3,并且如果异丙醚的加入太快,例如在少于5分钟的时间内,高度浓缩的粗化合物就会快速沉淀,形成浓厚的不可过滤的淤浆,化合物就会掺入大量由溶剂和溶于其中的杂质组成的母液,它会非常难以分离。而且,当分离和干燥时,它会包括大量杂质。
此外,存在高百分比的无定形状态的化合物,并且如之前所强调的,当包括在吸入制剂中时,无定形结构的颗粒会引起很多问题:事实上这类颗粒非常地粘合,倾向于粘在一起,并且在一定时间内倾向于在它的表面吸收周围的湿气。
因此,需要具有足够纯度和足够结晶度的化合物。
本发明提供了纯净结晶形式的CHF 4226及其制备方法。
为了制备本发明的结晶化合物,已经例如根据EP 0 147 719中公开的方法从乙醇、水和异丙醚的混合物中结晶获得的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐粗品要从适当的溶剂中重结晶。
适当的重结晶溶剂是质子溶剂,例如乙醇、异丙醇或它们的含水混合物。优选的溶剂是乙醇-水混合物。
最适合的重结晶溶剂是比例为97∶3-95∶5v/v的乙醇-水混合物。有利地,在将粗化合物溶解于上述溶剂中之后,和在分离最终产物之前,进行减压蒸馏乙醇水溶液的中间步骤,以从混合物中除去残留异丙醚并提高产率。
优选地,持续进行蒸馏操作,直至溶液减少至最初体积的1/2到1/3之间。
本发明的重结晶操作能有效除去杂质至等于或低于0.5%,优选0.2%,更优选0.1%的水平,以获得纯净结晶形式的、具有用于与适当 载体或赋形剂组合制备用于吸入的药物组合物的适当特性的化合物。
发明的详细描述
EP 0 147 719的方法,它的教导被全文引入本申请,包括过滤和用乙醇水溶液洗涤8-苯甲氧基-5-{(1R)-1-羟基-2-[N-((1R)-2-(对甲氧苯基)-1-甲基-乙基)氨基]乙基)喹诺酮盐酸盐催化氢化之后获得的混悬液,以除去催化剂。减压浓缩该溶液以除去溶剂。根据本发明,除去溶剂后获得的剩余物通过加热溶解于优选比例为95∶5的乙醇和水的混合物中,优选在200到400毫巴之间,在30℃到55℃之间,优选在45到50℃的温度下将如此获得的溶液减压浓缩,至最初体积的1/2到1/3之间。然后在搅拌下将异丙醚缓慢加至温热的溶液中。在至少5分钟内,优选在大于10分钟内,更优选在20到30分钟的时间内进行异丙醚的加入。
然后用1到2小时在搅拌下将混合物冷却至0℃到10℃,分离固体,并用乙醇洗涤。
将湿的粗产物混悬在乙醇中,在75-78℃下回流加热,缓慢加入水直至获得澄明溶液。过滤该溶液,用乙醇洗涤滤器。在不低于40℃,优选在40到50℃之间,更优选在45到48℃之间的温度下,搅拌并减压浓缩温热的溶液至体积为起始体积的约1/2到约1/3。产物开始从溶液中结晶生成混悬液。在搅拌下缓慢冷却混悬液,并保持在约0到10℃,优选约0到5℃的温度下,保持至少1小时,直至20小时或更长时间。过滤回收固体,用乙醇洗涤,最后以常规方式干燥,例如通过风干、减压干燥、或在无菌惰性气体的存在下干燥,以得到结晶化合物。
研究使用上述方法获得的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐,以测定:用差示扫描量热法(DSC)测定熔点,特定旋光功率[α]D 20,通过毛细管区带电泳法和通过高效液相色谱法(HPLC)测定对映异构纯度,通过HPLC和X-射线粉末衍射(XRD)图测定杂质总量。
本发明的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐通过以下参数表征:
以10℃/分钟的扫描速度用DSC测得180-200℃(分解),优选185-195℃(分解),更优选190-195℃(分解)的熔距;
-68.0°的特定旋光功率[α]D 20(c=1.00,甲醇);
用毛细管区带电泳法和用HPLC测得的高于99.0%,优选高于99.5%的对映异构纯度;
用HPLC测得的低于0.5%,优选低于0.2%,更优选低于0.1%的杂质水平;
与下列实施例所列相同或基本相同的X-射线粉末衍射图。该化合物尤其合适地具有一个或多个下列XRD特征峰:12.2;13.6;16.3;18.0;18.2;19.2;21.4;21.9;22.8;23.5;24.2;24.9;26.6;28.5;29.4;29.9;和33.9±0.2度/2θ;
结晶度表示成结晶化合物相对于化合物总重量的重量%,为至少90%,优选至少93%,甚至更优选至少95%,用室内进行(developedin-house)的微量量热法测定。
下列实施例举例说明了本发明。
实施例
8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐(CHF 4226单盐酸盐)的结晶
为了制备本发明的结晶状CHF 4226,例如已经在EP 0 147 719的实施例4的步骤3-a中所述的8-苯甲氧基-5-{(1R)-1-羟基-2-[N-((1R)-2-(对甲氧苯基)-1-甲基乙基)氨基]乙基}喹诺酮盐酸盐(100g)催化氢化之后获得的剩余物溶于约1300ml乙醇和100ml水中,并在旋转蒸发器中(水浴温度=55℃;真空度=-0.8巴)浓缩至剩余体积约为600ml。在30分钟内将异丙醚(560ml)滴入温热的溶液中(T=45-50℃)。将混合物冷却至5-10℃,并搅拌60分钟直至结晶过程完成,然后在Buckner过滤器中过滤,用200ml乙醇洗涤固体。
将湿的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐粗产物(154.6g;如果60℃真空干燥则相当于73g)混悬在乙醇(580ml)中,并在78℃下回流加热该混悬液;缓慢滴入25ml水,直至获得澄明溶液。在Buckner过滤器中过滤热溶液,用150ml乙醇洗涤。真空浓缩滤液(水浴温度=55-65℃;真空度=250-300毫巴;溶液温度=45-48℃),蒸馏约360ml溶剂。切断真空,将390ml乙醇加到剩余的混悬液中,在45℃下搅拌直至获得均一的混悬液。在90分钟内将该混悬液冷却至低于5℃,然后保持在5℃20小时。在Buckner过滤器中过滤混悬液,用150ml乙醇洗涤。然后在60℃下真空干燥该固体24小时。得到58.4g 8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2-(1H)-喹啉酮单盐酸盐(产率80.0%),它具有下列特征:
-以10℃/分钟的扫描速度用DSC测得熔距为190-194℃(分解);
-特定旋光功率[α]D 20(c=1.00甲醇)=-68.0°;
-用毛细管区带电泳法测得对映异构纯度高于99.5%;
-总杂质:低于0.1%;
-X-射线粉末衍射图(XRD)显示在图1中,用下列主峰表示:
角度[°/2θ] | Rel.Int.[%] |
12.3 | 21.0 |
13.6 | 54.2 |
16.4 | 64.9 |
18.0 | 37.5 |
18.4 | 44.5 |
19.3 | 50.1 |
21.4 | 55.8 |
21.9 | 100.0 |
22.9 | 35.6 |
23.6 | 36.9 |
24.3 | 88.4 |
25.0 | 21.4 |
26.7 | 32.5 |
28.6 | 22.6 |
29.5 | 30.5 |
29.9 | 14.8 |
34.0 | 20.4 |
[0061] 根据室内进行的以测量熔融热能为基础的差示扫描量热法(DSC)测定化合物的结晶度。
通过测定样品的ΔH(熔融热能)相对于100%结晶参比标准的ΔH的比率(后者在相同的温度范围内和在相同的实验条件下测定),所述方法使用130℃/分钟的扫描速度评价样品中结晶化合物的百分数。通过将化合物混悬在乙醇中,然后过滤以除去溶于乙醇的残留无定形化合物,并干燥,制备100%结晶参比标准。
这样操作以后,和研磨或微粉化之后,将该方法应用于实施例化合物的样品。所有样品都显示出了高于90%的结晶度,将化合物进行研磨和微粉化操作之后还保持了这样高的结晶度。
Claims (7)
1.8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐的结晶,其特征在于,用差示扫描量热法测得熔距为180-200℃,和具有下列特征峰的X-射线粉末衍射图:12.2;13.6;16.3;18.0;18.2;19.2;21.4;21.9;22.8;23.5;24.2;24.9;26.6;28.5;29.4;29.9;和33.9±0.2度/2θ。
2.权利要求1的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐的结晶,其特征在于,用差示扫描量热法测得的熔距为185-195℃。
3.权利要求1或2的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐的结晶,它具有至少90%的表示成结晶化合物相对于化合物总重量的重量%的结晶度。
4.权利要求1或2的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐的结晶,它具有至少93%的表示成结晶化合物相对于化合物总重量的重量%的结晶度。
5.权利要求1或2的8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐的结晶,它具有至少95%的表示成结晶化合物相对于化合物总重量的重量%的结晶度。
6.制备如权利要求1-5中任一项的结晶的方法,包括从添加了二异丙醚的97∶3-95∶5v/v的乙醇水混合物中将化合物8-羟基-5-[(1R)-1-羟基-2-[[(1R)-2-(4-甲氧苯基)-1-甲基乙基]氨基]乙基]-2(1H)-喹啉酮单盐酸盐结晶或重结晶,其中,所述乙醇水混合物在200到400毫巴之间,在30℃到55℃之间温度下减压浓缩至最初体积的1/2到1/3之间,且二异丙醚的添加至少进行5分钟。
7.根据权利要求6的方法,进一步包括从质子溶剂中重结晶的步骤,所述质子溶剂包括乙醇、异丙醇或它们的含水混合物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4579854A (en) * | 1983-12-24 | 1986-04-01 | Tanabe Seiyaku Co., Ltd. | Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4579854A (en) * | 1983-12-24 | 1986-04-01 | Tanabe Seiyaku Co., Ltd. | Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril |
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EA200601531A1 (ru) | 2007-04-27 |
WO2005089760A1 (en) | 2005-09-29 |
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NZ550010A (en) | 2010-08-27 |
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